Omicron was an unpleasant surprise in many ways. First, Spike and the overwhelming number of mutations throughout the genome produce other important effects, such as resistance to multiple vaccines and modified cellular entry. Second, Omicron is now known to be not one, but a distinct family of types—BA.1, BA.2, BA.3, and recombinant BA.4. Third, the Omicron family is more contagious than any other type before it. BA.1 is more contagious than Delta and BA.2 is more contagious than BA.1.
Here we address another unpleasant surprise from Omicron. In addition to being highly resistant to many vaccines, the family of variants is also resistant to currently available monoclonal antibodies, which are often the first line of defense for treating people who are infected but not yet critically ill. in a hospital setting. Antibodies developed to treat infections resulting from the original Wuhan virus or the early B.1 variant have reduced effectiveness against Omicron.
Evushield and bebtelovimab are two examples of antibodies with low micron neutralization. Both antibody treatments target binding sites that are mutated into the Omicron receptor-binding domain. Among the targeted residues of Evushield, S477, T478, E484 and Q493 are all changed to BA.1, BA.1.1 and BA.2. The binding map of bebtelovimab is also altered at positions N440, G446, Q498, and N501.
Thankfully, there are some antibodies that can still cause significant neutralization of the omicron family. These could become the next great tool in the fight against severe COVID-19. Here we describe a study by Fenwick and others. which describes these antibody candidates and how they are able to neutralize BA.1, BA.2 and all their subtypes.
Screening for the presence of anti-spike antibodies in over 100 samples from sera donors, Fenwick and others. Identified two monoclonal antibody candidates that showed promising results against previous forms of anxiety, including alpha, beta, gamma and delta. They compared these two antibodies to currently available monoclonal treatments, such as the AstraZeneca combination cocktail, Regeneron cocktail, and sotrovimab.
Two antibodies, P2G3 and P5C3, not only suppressed the Wuhan strain of SARS-CoV-2, but also significantly affected alpha, beta, gamma, delta and, notably, BA.1, BA.1.1, and BA.2. neutralized by. Effectively. P2G3 was 5 to 907-fold more potent at inactivating the oomicron family spike proteins than other monoclonal treatments. P5C3 was slightly less potent than P2G3, but still more inactive than the other treatments tested.
In particular, Fenwick and others. identified on cryo-electron microscopy that P5C3 bound the virus non-competitively with P2G3, meaning that they could be combined in a single treatment. This combination by itself performed roughly the same as P2G3, although we note that a combination would be more difficult for the virus to mutate.
Both are non-competitive as they bind to the spike receptor-binding domain at different angles. The authors believe that P5C3 takes a general approach as previous monoclonal antibodies, latching to the up-configuration of the receptor-binding domain. P2G3 attacks at an unusual angle, targeting the side of the protein rather than the top, meaning the antibody can bind in an up or down configuration. Together, the antibodies effectively lock the spike protein in place, limiting its transmission.
During pandemics, our latest defenses against serious illness have changed in various ways. Just as Omicron mutates multiple spike and genome-wide mutations that reduce the effectiveness of vaccines and monoclonal therapies, future variants may mutate to overcome P2G3 and P5C3. When administered simultaneously, we are essentially delaying that process by giving the virus more targets to mutate.
Recent studies of antibodies to sotrovimab indicate that resistance to treatment, when used as a monotherapy, increases rapidly in treated patients. especially in people who are immunosuppressed, rocket and others. Note that over time, infected hosts with persistent infection may develop mutant viruses that reduce sotrovimab neutralization by up to 300-fold.
We suggest avoiding the monotherapy approach of antibodies altogether. There are several monoclonal antibodies that bind to relatively conserved sites in SARS-CoV-2 variants. Among these is the S2K146 antibody to Vir/GSK, which uses a wide footprint to remove heavily mutated sites such as N501 and E484. The second is a CV3-1 monoclonal antibody that binds to the 485-GFN-487 loop in the receptor-binding domain, a highly conserved site in Omicron and other variants.
A third is CV3-25, which completely avoids the receptor-binding domain and inhibits the spike protein via the S2 region. This is of particular interest because it binds completely to a different region than the receptor-binding domain.
Now that there are many antibodies available, and more to come, we must combine at least three or more of the described antibodies in a single treatment, making the task of overcoming neutralization more difficult for the virus. One of the antibodies involved must certainly be CV3-25, as it differs from most of the circulating antibody candidates so far. Ultimately, SARS-CoV-2 will continue to replace and overcome our devices for months and perhaps years to come. During such times, we must continue to develop and innovate strategies to fight serious disease, and combination monoclonal therapy is one such approach.